ZHANG ET AL.
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Methyl 4-((3-chloro-4-(3-fluorobenzyl)sulfonylphenyl)amino)-
DMSO) δ (ppm): 10.29 (s, 1H), 8.78 (s, 1H), 7.60–7.53 (m, 2H), 7.43 (dd,
J = 10.8, 5.1 Hz, 2H), 7.32–7.24 (m, 3H), 7.20 (d, J = 7.7 Hz, 2H), 4.73 (d,
J = 5.7 Hz, 2H), 3.89 (d, J = 5.5 Hz, 2H), 3.03 (d, J = 5.8 Hz, 2H).
7
,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (5k)
From 4a and 3-chloro-4-(3-fluorobenzyl)sulfonylaniline as starting
materials. Yield: 44.0%; m.p.: 198.9–201.1°C; MS (ESI) m/z: 491
+
1
[
M+H] ; H NMR (400 MHz, DMSO-d
H), 8.26 (d, J = 2.0 Hz, 1H), 7.85 (dd, J = 8.8, 1.8 Hz, 1H), 7.64 (d,
J = 8.9 Hz, 1H), 7.37–7.30 (m, 1H), 7.15 (td, J = 8.6, 2.4 Hz, 1H), 7.03 (m,
H), 4.82 (s, 2H), 4.55 (s, 2H), 3.70–3.65 (m, 5H), 2.78 (t, J = 5.7 Hz, 2H).
Anal. calcd. for C22 20ClFN S (%): C, 53.82; H, 4.11; N, 11.41.
6
) δ (ppm): 9.07 (s, 1H), 8.57 (s,
N-(3-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]
pyrimidine-4-amine (6)
1
A mixture solution of 5l (14.0 g, 0.033 mol) in acetic acid (28 mL) and
HBr (28 mL) was warmed to 50°C and stirred for 5 h. After completion
of the reaction as indicated by TLC, the reaction mixture was cooled to
room temperature and poured into ice water (100 mL), which was
basified with 15% NaOH to pH 10. The resultant precipitate was
filtered, washed with water, and air-dried to furnish compound 6 (7.5 g,
2
H
4 4
O
Found (%): C, 53.64; H, 4.04; N, 11.28.
Benzyl 4-((3-(trifluoromethyl)phenyl)amino)-7,8-
+
dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (5l)
From 4c and 3-trifluoromethylaniline as starting materials. Yield:
78.1%) as yellow solid. MS (ESI) m/z: 295.1 [M+H] .
+
1
5
3.9%; m.p.:213.3–214.9°C; MS (ESI) m/z: 429.1 [M+H] ; H NMR
2-Chloroethyl 4-((3-(trifluoromethyl)phenyl)amino)-7,8-
(
(
(
(
400 MHz, DMSO) δ (ppm): 10.21 (s, 1H), 8.80 (s, 1H), 7.98 (s, 1H), 7.92
d, J = 8.2 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.32
t, J = 7.9 Hz, 2H), 7.23 (t, J = 7.5 Hz, 1H), 7.11 (d, J = 7.7 Hz, 2H), 4.86
s, 2H), 4.72 (d, J = 5.7 Hz, 2H), 3.88 (d, J = 5.5 Hz, 2H), 3.02 (d,
dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (7)
2 2
To a solution of 6 (2.0 g, 0.007 mol) in CH Cl (20 mL), DIPEA (1.3 g,
0.010 mol) and 2-chloroethyl carbonochloridate (1.3 g, 0.009 mol)
were added under stirring at 0°C. The mixture was heated to room
temperature and stirred for 3 h. After completion of the reaction as
indicated by TLC, the mixture was poured into water 30 mL, and the
organic layer was washed with brine (30 mL × 2) and dried over
J = 5.8 Hz, 2H). Anal. calcd. for C22
19 3 4 2
H F N O (%): C, 61.68; H, 4.47; N,
1
3.08. Found (%): C, 61.49; H, 4.14; N, 13.00.
Phenyl 4-((3-(trifluoromethyl)phenyl)amino)-7,8-
anhydrous Na
2 4
SO and concentrated in vacuo. The residue was
dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (5m)
From 4b and 3-(trifluoromethyl)aniline as starting materials. Yield:
collected and air-dried to obtain compound 7 (2.2 g, 78.9%) as yellow
+
1
solid. M.p.: 196.7–198.5°C; MS (ESI) m/z: 491 [M+H] ; H NMR
(400 MHz, MeOD) δ (ppm): 8.42 (s, 1H), 8.03 (s, 1H), 7.89 (d, J = 8.1 Hz,
1H), 7.48 (t, J = 7.9 Hz, 1H), 7.36 (d, J = 7.7 Hz, 1H), 4.58 (m, 2H), 4.39 (t,
J = 5.4 Hz, 2H), 3.84–3.77 (m, 4H), 2.82 (t, J = 5.8 Hz, 2H).
+
1
5
1.2%; m.p.: 247.9–248.6°C; MS (ESI) m/z: 415.1 [M+H] ; H NMR
(400 MHz, DMSO) δ (ppm): 10.25 (s, 1H), 8.83 (s, 1H), 7.99 (s, 1H), 7.95
(d, J = 8.3 Hz, 1H), 7.67 (t, J = 7.9 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.42
(t, J = 7.9 Hz, 2H), 7.25 (t, J = 7.4 Hz, 1H), 7.20 (d, J = 7.8 Hz, 2H), 4.77
(d, J = 5.7 Hz, 2H), 3.88 (d, J = 5.5 Hz, 2H), 3.03 (d, J = 5.6 Hz, 2H).
4
.1.6 General procedure for the preparation of
|
compounds 8a–e
Phenyl 4-((3-isopropylphenyl)amino)-7,8-dihydropyrido[4,3-d]
pyrimidine-6(5H)-carboxylate (5n)
To a solution of 7 (5.0 g, 0.012 mol) in DMF (100 mL), substituted
aniline (0.072 mol), DIPEA (3.1 g, 0.024 mol), and KI (0.3 g, 0.002 mol)
were added subsequently under stirring at room temperature. The
mixture solution was heated to 80°C for 6 h. After completion of the
reaction as indicated by TLC, the reaction mixture was cooled to room
temperature and poured into ice water (200 mL) slowly. The resultant
From 4b and 3-isopropylaniline as starting materials. Yield: 46.1%; m.p.:
+
1
2
51.0–254.3°C; MS (ESI) m/z: 389.2 [M+H] ; H NMR (400 MHz, DMSO)
δ (ppm): 10.19 (s, 1H), 8.76 (s, 1H), 7.42 (dd, J = 11.6, 5.4 Hz, 4H), 7.30 (d,
J = 8.5 Hz, 2H), 7.27 (dd, J = 10.4, 4.3 Hz, 1H), 7.20 (d, J = 7.8 Hz, 2H), 4.72
(d, J = 5.7 Hz, 2H), 3.88 (d, J = 5.5 Hz, 2H), 3.02 (d, J = 5.8 Hz, 2H).
mixture was extracted with CH
combined organic layer was washed with water and dried over
MgSO . After filtration, the solvent was concentrated in vacuo and the
resulting precipitate was filtered to furnish crude product. The crude
2
product was purified by chromatography on silica gel using CH Cl /
2 2
Cl (50 mL × 2) twice, and the
Phenyl 4-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]
pyrimidine-6(5H)-carboxylate (5o)
4
From 4b and 3-chloroaniline as starting materials. Yield: 41.1%; m.p.:
+
1
2
37.6–238.7°C; MS (ESI) m/z: 380.1 [M+H] ; H NMR (400 MHz,
2
DMSO) δ (ppm): 10.21 (s, 1H), 8.80 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.50
MeOH (10:1) to afford the desired compounds 8a–e as pale yellow
(
(
(
d, J = 8.8 Hz, 2H), 7.43 (t, J = 7.9 Hz, 2H), 7.26 (t, J = 7.4 Hz, 1H), 7.20
solid.
d, J = 7.9 Hz, 2H), 4.74 (d, J = 5.7 Hz, 2H), 3.88 (d, J = 5.6 Hz, 2H), 3.02
d, J = 5.7 Hz, 2H). Anal. calcd. for C20
H
17ClN
4
O
2
(%): C, 63.08; H, 4.50;
2-(Dimethylamino)ethyl 4-((3-(trifluoromethyl)phenyl)amino)-
7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (8a)
From dimethylamino as starting material. Yield: 24.5%; m.p.: 189.1–
N, 14.71. Found (%): C, 63.14; H, 4.24; N, 14.48.
−
1
Phenyl 4-((3-fluorophenyl)amino)-7,8-dihydropyrido[4,3-d]
pyrimidine-6(5H)-carboxylate (5p)
3
191.6°C; MS (ESI) m/z: 407.9 [M−H] ; H NMR (400 MHz, CDCl ) δ
(ppm): 8.57 (s, 1H), 8.31 (s, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.46 (t,
J = 8.0 Hz, 1H), 7.35 (d, J = 7.7 Hz, 1H), 5.00 (s, 2H), 4.50–4.45 (m, 2H),
3.84 (t, J = 5.9 Hz, 2H), 3.39 (s, 2H), 3.02–2.92 (m, 8H). Anal. calcd. for
From 4b and 3-fluoroaniline as starting materials. Yield: 46.2%; m.p.:
+
1
2
90.1–292.0°C; MS (ESI) m/z: 364.1 [M+H] ; H NMR (400 MHz,